PRACTICAL ISSUES OF ANTICOAGULANT ACCEPTANCE IN

AVIATION MEDICINE

S. BISCONTE(1), A. HORNEZ(2), J. MONIN(2), D. DUBOURDIEU(2), X. ZIRPHILE(3), S. NGUYEN(1), O. MANEN(2),E. PERRIER(2).

87th ASMA ANNUAL SCIENTIFIC MEETING

ATLANTIC CITY - April 24 - 28, 2016

(1) Aeromedical Center, Robert Picqué Military Hospital, Bordeaux, France (2) Aeromedical Center, Percy Military Hospital, Clamart, France

(3) Cardiology, Robert Picqué Military Hospital, Bordeaux, France

Disclosure Information 87th AsMA Annual Scientific Meeting

Sebastien BISCONTE

I have no financial relationships to disclose.

I will not discuss off-label use or

investigational use in my presentation.

For 60 years, vitamin K antagonists (e.g., warfarin sodium) were the only available oral anticoagulant medications

Benefit / Risk Balance ! incapacitation !Thromboembolism .. stroke ! Intra cranial bleeding… ! consequences on flight safety

Evolution of knowledge ! Fit to fly with limitations

! Raises new problems for the flight surgeon

The advent of Direct Oral Anticoagulants (DOACs)

First use in France : 2008

! Raises some problems for the flight surgeon

We will only discuss about oral medication: VKA & DOACs heparin, specific anticoagulants (danaparoïde…)

Only prophylaxic treatment

Why were VKA initially prohibited for pilots ?

It’s a family problem:

"   an unpredictable dose-response relationship

"  multiple drug interactions

"  multiple diet interactions

! Narrow therapeutic index

Variable dietary control during flight can cause problems.

Why were VKA initially prohibited for pilots ?

It’s a family problem:

!  Narrow therapeutic index

"   <65% of time in the therapeutic zone

"   0.25% fatal bleeding

"   1% major bleeding

"   6.5% minor bleeding

#  15% of patients having at least one minor event a year

Initially Prohibited for pilots in France

Stroke Intracranial Bleeding

Flight safety

Palareti Lancet 1996

Medical regulation changes

Why ? -   Limited bleeding risk in the

therapeutic zone

-   Knowledge on anticoagulants in specific population

« young » population No comorbidity High intellectual ability

Medical regulation changes

Why ? -   Limited bleeding risk in the

therapeutic zone

-   Knowledge on anticoagulants in specific population

-   Identification of bleeding risk factor

Major bleeding risk : - intracranial hemorrhage,

- bleeding requiring hospitalization, - Hb drop of more than 2g/dL for systemic anticoagulation in pts with atrial fibrillation

Camm AJ. Eur Heart J. 2010 Pisters R. Chest. 2010 .Lip GYHEuropace. 2011

Medical regulation changes

Why ? -   Knowledge on anticoagulants

and take into account work accidentology due to VKA

-   Limited risk in the therapeutic zone

-   Identification of bleeding risk factor (limited in air crew members)

-   French to European regulation

European regulation for civil aircrew Implementing Rules:

« Applicants with an established history or diagnosis of cardiovascular condition requiring systemic anticoagulant therapy

shall be referred to the licencing authority »

Acceptable means of compliance

Referred to the licencing authority Multi-pilot limitation

-   What is really a stable anticoagulation ? « 6-5-4 rule »

What about DOACs?

Case report

Pilote – 50 yo Class 3 50 flight hours -   Aortic dissection -   Stanford type A -   Biscupid aortic valve

! Bentall procedure Treatment: Bisoprolol 5mg

Fluindione 20mg

Is VKA the only problem ?

First step: evaluation of underlying disease

Case report

Pilote – 50 yo Class 3 50 flight hours -   Aortic dissection -   Stanford type A -   Biscupid aortic valve

! Bentall procedure No surgery complication Asymptomatic Good fonction of the mechanical

valve No arrythmias Treatment: Bisoprolol 5mg

Fluindione 20mg

First step: evaluation of underlying disease

Is VKA the only problem ?

o   Symptoms o   Complications o   Prognosis o   Consequences on flight safety

o   … and treatment

Case report

Pilote – 50 yo Class 3 50 flight hours -   Aortic dissection -   Stanford type A -   Biscupid aortic valve

! Bentall procedure No surgery complication Asymptomatic Good fonction of the mechanical

valve No arrythmias Treatment: Bisoprolol 5mg

Fluindione 20mg

Stable anticoagulation ? !   6-5-4 Rule !   INR target range : 2-3

month

Case report

Pilote – 50 yo Class 3 50 flight hours -   Aortic dissection -   Stanford type A -   Biscupid aortic valve

! Bentall procédure No surgery complication Asymptomatic Good fonction of the mechanical

valve No arrythmias Treatment: Bisoprolol 5mg

Fluindione 20mg

Stable anticoagulation ? !   6-5-4 Rule !   INR target range : 2-3

month

Case report

Pilote – 50 yo Class 3 50 flight hours -   Aortic dissection -   Stanford type A -   Biscupid aortic valve

! Bentall procédure No surgery complication Asymptomatic Good fonction of the mechanical

valve No arrythmias Treatment: Bisoprolol 5mg

Fluindione 20mg

Stable anticoagulation ? !   6-5-4 Rule !   INR target range : 2-3

month

6-5-4 rule is a theoretical rule Anticoagulant stability is a case by

case medical evaluation

Case by case evaluation

the significance of abnormal INR depends on the medical condition

Bleeding

Thromboembolism Thromboembolism CHA2DS2 VASC

HASBLED

Bleeding

If phlebitis

If aortic valve

Prophylaxis only

Bleeding

Thromboembolism

- Dabigatran

- Apixaban

- Rivaroxaban

- Edoxaban

•  Prophylaxisinorthopaedics

•  Prophylaxisinnon-valvularAfib•  TreatmentandprophylaxisofrecurrenceinTEdisease

•  NotformechanicalvalveApprovedEMA/FDA;notinFrance

UpdatedEuropeanHeartRhythmAssocia?onPrac?calGuideontheuseofnon-vitaminKantagonistan?coagulantsinpa?entswithnon-valvularatrialfibrilla?on.HeinHeidbuchel,PeterVerhamme,MarcoAlings,MaDhiasAntz,Hans-ChristophDiener,WernerHacke,JonasOldgren,PeterSinnaeve,A.JohnCamm,andPaulusKirchhof.Europacedoi:10.1093/europace/euv309

Different DOACs

Efficacy: DOACs vs VKA

At least as effective as VKA

Dataregardingfulldosage.

Chris?anTRuff,RobertPGiugliano,EugeneBraunwald,ElaineBHoffman,NaveenDeenadayalu,MichaelDEzekowitz,AJohnCamm,JeffreyIWeitz,BasilSLewis,AlexanderParkhomenko,TakeshiYamashita,EllioTMAntman.ComparisonoftheefficacyandsafetyofneworalanQcoagulantswithwarfarininpaQentswithatrialfibrillaQon:ameta-analysisofrandomisedtrials.Lancet2014;383:955–62.

Safety: DOACs vs VKA

Less major bleeding. Less Intracranial bleeding.

More GI bleeding.

Chris?anTRuff,RobertPGiugliano,EugeneBraunwald,ElaineBHoffman,NaveenDeenadayalu,MichaelDEzekowitz,AJohnCamm,JeffreyIWeitz,BasilSLewis,AlexanderParkhomenko,TakeshiYamashita,EllioTMAntman.ComparisonoftheefficacyandsafetyofneworalanQcoagulantswithwarfarininpaQentswithatrialfibrillaQon:ameta-analysisofrandomisedtrials.Lancet2014;383:955–62.

DOACs interactions

Some drug interactions But no diet interaction

Possiblemonitoring

Possiblesupervision

DOACs monitoring

Without proportionality

Expensive…

Elimina?onhalf-life

DOACs vs DOACs

•  NoDOACsVsDOACsstudy.•  Atfulldosage:

ApixabanVsVKA:seemstobemoresaferDabigatranVsVKA:seemstobemoreefficient

•  Nearhalf-life-->samestabilityConnolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med.

17 sept 2009;361(12):1139‑1151. (RE-LY). Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus Warfarin in the Treatment of Acute Venous

Thromboembolism. N Engl J Med. 10 déc 2009;361(24):2342‑2352. (RECOVER). Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med. 8 sept

2011;365(10):883‑891. (ROCKET-AF). The Einstein Investigators, Rupert Bauersachs, Scott D. Berkowitz, Benjamin Brenner. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. N

Engl J Med. 23 déc 2010;363(26):2499‑2510. (EINSTEIN). Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med.

15 sept 2011;365(11):981‑992. (ARISTOTLE). Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. N Engl J Med.

29 août 2013;369(9):799‑808. (AMPLIFY). Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med.

2013;369(22):2093–2104. (ENGAGE-AF). Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–15.

(HOKUSAI).

Place of DOACs in aviation medicine

Use DOACs doesn’t change: •   evaluation of underlying

cardiopathy

•   Requirement to refer to the licencing authority

•   Requirement of Multi-pilot limitation

Main Advantages of DOACs : •   At least as effective as VKA •   Less intracranial bleeding •   Less overall bleeding •   No diet interaction •   Less drug interactions

Main Disadvantages of DOACs: •   Short half-time •   Monitoring not easy

! New problematic compliance?

DOACs compliance

Pharmocalogical test: - very expensive - without proportionnality

Short Half life ! stability of the last

few days Quality of relationship between

Aircrew members and fight surgeon +++

- Understand his disease - Importance of daily compliance

Aircrew members/flight surgeon relationship

If you have a reasonnable doubt and for first evaluation:

- Number and dates of prescriptions ! PT or aPTT

Delay ?

! 3 months

The perfect anticoagulant still remains elusive; That’s why referring to licensing authority and multi pilot

license is always necessary .

However, the advent of the direct oral anticoagulants represents a real improvement.

DOACs are at least as safe and efficient as VKAs. The monitoring compliance difficulties

are not a real problem.

Like all new treatment in aviation medicine, anticoagulants require long term survey.

Take home message

Thank you for your attention